Dysfunction of the serotonergic system is considered to play a central role in the genesis of major depression and schizophrenia. In particular, the 5-HT2A receptor has been implicated in the pathophysiology of depression and schizophrenia and as the site of action of various psychotherapeutic agents. The most important and consistent finding of serotonergic dysfunction in major depression is increased B of the S-HT2A receptor. This has been documented in the CNS and in the periphery of depressives. The molecular mechanisms that underlie the changes in receptor expression in depression are not understood. The objectives of this proposal are to identify and characterize the factors that regulate the expression of the 5-HT2A receptor, and relate those mechanisms to the pathophysiology of depression. Three Specific Aims are proposed that examine the different levels of regulation of the receptor. The goal of the first Specific Aim is to map genes that control the level of expression of the 5-HT2A receptor in the brain, and begin to identify those genes. This will be accomplished through genetic analysis of Recombinant Inbred (RI) strains of mice, with QTL analysis. The final step in the genetic analysis will be to identify the relevant genes. The experiments in this Aim will also test whether the same genes control the expression of the receptor throughout the body. The goal of the second Specific Aim is to identify critical elements in the promoter for the S-HT2A gene that direct cell specific expression of the receptor. A series of transgenic animals will be produced that have different versions of the S-HT2A promoter driving expression of a reporter gene. The hypothesis tested is that the expression of the receptor is controlled by the interplay of positive and negative response elements in the receptor promoter. The goal of the third Specific Aim is to determine whether a number of growth factors control the expression of the S-HT2A receptor. These experiments will use a number of cells in culture that express the S-HT2A receptor. These cells have been derived from both the CNS and peripheral tissues. The factors that will be tested include glucocorticoids, and a series of immune regulators. These factors are known to be altered in depression and can exert powerful regulatory influences on the expression of a number of genes. As the factors are characterized in the in vitro systems, their relevance to the regulation of the S-HT2A receptor in the brain will be tested in experimental animals.